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Randomized Controlled Trial
. 2014 Dec;9(12):1973-83.
doi: 10.1093/scan/nsu018. Epub 2014 Feb 3.

Long-term Expression of Human Contextual Fear and Extinction Memories Involves Amygdala, Hippocampus and Ventromedial Prefrontal Cortex: A Reinstatement Study in Two Independent Samples

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Free PMC article
Randomized Controlled Trial

Long-term Expression of Human Contextual Fear and Extinction Memories Involves Amygdala, Hippocampus and Ventromedial Prefrontal Cortex: A Reinstatement Study in Two Independent Samples

Tina B Lonsdorf et al. Soc Cogn Affect Neurosci. .
Free PMC article

Abstract

Human context conditioning studies have focused on acquisition and extinction. Subsequent long-term changes in fear behaviors not only depend on associative learning processes during those phases but also on memory consolidation processes and the later ability to retrieve and express fear and extinction memories. Clinical theories explain relapse after successful exposure-based treatment with return of fear memories and remission with stable extinction memory expression. We probed contextual fear and extinction memories 1 week (Day8) after conditioning (Day1) and subsequent extinction (Day2) by presenting conditioned contexts before (Test1) and after (Test2) a reinstatement manipulation. We find consistent activation patterns in two independent samples: activation of a subgenual part of the ventromedial prefrontal cortex before reinstatement (Test1) and (albeit with different temporal profiles between samples) of the amygdala after reinstatement (Test2) as well as up-regulation of anterior hippocampus activity after reinstatement (Test2 > Test1). These areas have earlier been implicated in the expression of cued extinction and fear memories. The present results suggest a general role for these structures in defining the balance between fear and extinction memories, independent of the conditioning mode. The results are discussed in the light of hypotheses implicating the anterior hippocampus in the processing of situational ambiguity.

Keywords: amygdala; anterior hippocampus; phasic and sustained fear; reinstatement; return of fear.

Figures

Fig. 1
Fig. 1
Design. Experimental timeline (A) and structure of trials in the unpredictable (B), predictable (C) and safe (D) trials. Shown is an example of stimulus-condition assignments. Bolt denotes US.
Fig. 2
Fig. 2
Behavioral data. Fear ratings and SCRs for context CSs in the discovery (A, C) and replication samples (B, D) and for cue CSs in the discovery (E, G) and replication samples (F, H). PCXT, UCXT, SCXT: context CSs in the predictable, unpredictable and safe conditions, respectively. PCue, UCue, SCue: cue CSs in the predictable, unpredictable and safe conditions, respectively. Data show mean ± s.e.m. Log, logarithmized; rc, range-corrected. Bolt denotes reinstatement USs.
Fig. 3
Fig. 3
Imaging data, context conditioning: major findings from Test1 (before reinstatement) and Test2 (after reinstatement). Contrast UCXT > SCXT at Test1 in the vmPFC ROI in the discovery (A) and replication samples (B) as well as at Test2 in the dmPFC ROI in the discovery sample (C) and in the right amygdala ROI in the replication sample (D). Correlation of the SCR index for contextual fear (UCXT > SCXT) at Test2 with left amygdala activation at Test2 in the discovery sample (E). Statistical parametric maps are superimposed on an average structural image and thresholded at P = 0.01 on sagittal (A–C) or coronal (D, E) views, respectively. Red borders indicate the exact locations of the ROIs. Bar graphs show parameter estimates. *P(SVC) < 0.05.
Fig. 4
Fig. 4
Imaging data, context conditioning: reinstatement effects (Test2 > Test1). UCXT responses at Test2 > Test1 in the anterior hippocampus ROI in the discovery sample (A) and the right anterior hippocampus ROI in the replication sample (B) as well as in the left posterior hippocampus ROI in the discovery sample (C). Contrast PCXT at Test2 > Test1 in the left anterior hippocampus ROI in the discovery sample (D) and in the right anterior hippocampus ROI in the replication sample (E). Activations are superimposed on an average structural image and thresholded at P = 0.01 on coronal views. Bar graphs show parameter estimates. *P(SVC) < 0.05, #P(SVC) < 0.1.
Fig. 5
Fig. 5
Imaging data, cue conditioning: major findings from Test1 (before reinstatement) and Test2 (after reinstatement). Correlation of the SCR index for cued fear (PCue > SCue) at Test1 with left posterior hippocampus activation at Test1 in the discovery sample (A). Contrast PCue > SCue at Test2 in the vmPFC ROI in the discovery (B) and replication samples (C). Activations are superimposed on an average structural image and thresholded at P = 0.01 on coronal (A) or sagittal (B, C) views, respectively. Red borders indicate the exact locations of the ROIs. Bar graphs show parameter estimates. *P(SVC) < 0.05, #P(SVC) < 0.1.

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